Discoidin Domain Receptor 1 Regulates Runx2 during Osteogenesis of Osteoblasts and Promotes Bone Ossification via Phosphorylation of p38

• Main Authors: Liang-Yin Chou, Chung-Hwan Chen, Shu-Chun Chuang, Tsung-Lin Cheng, Yi-Hsiung Lin, Hsin-Chiao Chou, Yin-Chih Fu, Yan-Hsiung Wang, Chau-Zen Wang
• Format: Article
• Language: English
• Published: MDPI AG 2020-09-01
• Series: International Journal of Molecular Sciences
• Subjects: bone; discoidin domain receptor 1; DDR1; osteoblast; osteogenesis; bone development
• Online Access: https://www.mdpi.com/1422-0067/21/19/7210
• ISSN: 1661-6596; 1422-0067

Discoidin domain receptor 1 (<i>Drd1</i>) is a collagen-binding membrane protein, but its role in osteoblasts during osteogenesis remains undefined. We generated inducible osteoblast-specific <i>Ddr1</i> knockout (OKOΔ<i>Ddr1</i>) mice; their stature at birth, body weight and body length were significantly decreased compared with those of control <i>Ddr1^f/f-4OHT</i> mice. We hypothesize that <i>Ddr1</i> regulates osteogenesis of osteoblasts. Micro-CT showed that compared to 4-week-old <i>Ddr1^f/f-4OHT</i> mice, OKOΔ<i>Ddr1</i> mice presented significant decreases in cancellous bone volume and trabecular number and significant increases in trabecular separation. The cortical bone volume was decreased in OKOΔ<i>Ddr1</i> mice, resulting in decreased mechanical properties of femurs compared with those of <i>Ddr1^f/f-4OHT</i> mice. In femurs of 4-week-old OKOΔ<i>Ddr1</i> mice, H&E staining showed fewer osteocytes and decreased cortical bone thickness than <i>Ddr1^f/f-4OHT</i>. Osteoblast differentiation markers, including BMP2, Runx2, alkaline phosphatase (ALP), Col-I and OC, were decreased compared with those of control mice. <i>Ddr1</i> knockdown in osteoblasts resulted in decreased mineralization, ALP activity, phosphorylated p38 and protein levels of BMP2, Runx2, ALP, Col-I and OC during osteogenesis. Overexpression and knockdown of <i>Ddr1</i> in osteoblasts demonstrated that DDR1 mediates the expression and activity of Runx2 and the downstream osteogenesis markers during osteogenesis through regulation of p38 phosphorylation.